The role of short-term plasticity at the calyx of Held for auditory processing

耳萼短期可塑性对听觉处理的作用

• 批准号: 8737014
• 负责人: YunXiang Chu
• 金额: $ 4.77万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2017-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737014
• 关键词: Action Potentials; Auditory; Brain; Brain Stem; Calcium; Cell Nucleus; Cells; Central Auditory Processing Disorder; Chemosensitization; Cochlea; Contralateral; Data; Defect; Development; Drops; Electrophysiology (science); Environment; Etiology; Excitatory Synapse; Exhibits; Frequencies; Glutamates; Glycine; Goals; Hearing; Hearing problem; Human; Image; Imaging Techniques; Ipsilateral; Maps; Measures; Medial; Mediating; Mediator of activation protein; Microscopy; Modeling; Molecular; Molecular Genetics; Mutate; Neurons; Outcome; Pathway interactions; Phosphorylation Site; Physiological; Play; Probability; Procedures; Process; Protein Isoforms; Protein Kinase C; Proteins; Research; Research Proposals; Residual state; Rodent; Role; Shapes; Signal Transduction; Slice; Sound Localization; Specificity; Stimulus; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Temperature; Testing; Training; Transgenic Mice; Vesicle; Viral; calcium indicator; gamma-Aminobutyric Acid; information processing; insight; knock-down; lateral superior olive; medical schools; neuromechanism; neurotransmission; presynaptic; public health relevance; sound; transmission process; trapezoid body; two-photon

DESCRIPTION (provided by applicant): Defects in synaptic transmission in the auditory brainstem or cortex can give rise to central auditory processing disorders where the brain cannot correctly process sound. Investigating the synaptic mechanisms governing the processes of hearing in the auditory brainstem will allow for a better understanding of the etiology of human hearing disorders. The long-term objectives of the proposed research are to define the mechanisms that govern short-term plasticity at the auditory brainstem synapse called the calyx of Held, and to determine the functional importance of plasticity at this synapse for sound localization. The calyx of Held is a giant glutamatergic synapse in the auditory brainstem that functions as a fast excitatory synapse for sound localization. The calyx displays a form of short-term plasticity called post-tetanic potentiation (PTP), which can be induced by high-frequency (tetanic) stimulation and is dependent on elevations in presynaptic residual Ca2+ concentrations. Specifically, increases in presynaptic Ca2+ activate Ca2+-dependent isoforms of protein kinase C (PKCCa). While the calyx has long been studied as a model synapse, the physiological significance of PTP at the calyx has not been explored. Calyces are glutamatgeric synapses that project onto principal neurons of the medial nucleus of the trapezoid body (MNTB). The MNTB ?LSO synapse has been recently discovered to co-release glutamate/GABA/glycine during the period of synaptic refinement prior to hearing onset. Calyceal PTP is hypothesized to modulate the fidelity and temporal precision of MNTB firing remains unknown, and to increase release probability at the MNTB?LSO synapse to favor glutamatergic transmission. Thus, forms of short-term plasticity like PTP could play a major role in shaping the sound localization brainstem circuit. The specific aims of this research proposal are to (1) determine the dynamics of PTP under physiological conditions at the calyx of Held, (2) investigate the functional role of calyceal PTP in the brainstem sound localization pathway, and (3) dissect the PTP molecular cascade to selectively alter short-term plasticity at the calyx. The primary techniques used to achieve these aims include whole-cell electrophysiology recordings, bulk presynaptic Ca2+ loading in brain slices, and two-photon imaging of Ca2+ transients. The completion of this proposal will provide considerable insight into the functional roles of PTP at a key synapse in the auditory brainstem. The expertise of Dr. Wade Regehr and the environment of Harvard Medical School provide me with extensive training in electrophysiology and imaging techniques necessary to complete my goals.

描述（由申请人提供）：听觉脑干或皮质中的突触传递缺陷可能会导致中枢听觉处理障碍，使大脑无法正确处理声音。研究控制听觉脑干听觉过程的突触机制将有助于更好地了解人类听力障碍的病因。拟议研究的长期目标是定义控制听觉脑干突触（称为 Held 花萼）短期可塑性的机制，并确定该突触可塑性对于声音定位的功能重要性。 Held 的花萼是听觉脑干中的一个巨大的谷氨酸能突触，充当声音定位的快速兴奋性突触。花萼表现出一种称为强直后增强 (PTP) 的短期可塑性，它可以通过高频（强直）刺激诱导，并且取决于突触前残留 Ca2+ 浓度的升高。具体来说，突触前 Ca2+ 的增加会激活 Ca2+ 依赖性蛋白激酶 C (PKCCa) 亚型。虽然花萼长期以来被作为突触模型进行研究，但花萼 PTP 的生理意义尚未被探索。花萼是投射到梯形体内侧核（MNTB）主要神经元上的谷氨酸突触。最近发现 MNTB ?LSO 突触在听力出现前的突触细化期间共同释放谷氨酸/GABA/甘氨酸。假设肾盏 PTP 可以调节 MNTB 放电的保真度和时间精度，并且增加 MNTB?LSO 突触的释放概率以有利于谷氨酸能传递。因此，像 PTP 这样的短期可塑性形式可能在塑造声音定位脑干回路中发挥重要作用。本研究计划的具体目的是（1）确定生理条件下 Held 花萼处 PTP 的动态，（2）研究花萼 PTP 在脑干声音定位通路中的功能作用，以及（3）剖析 PTP 分子级联以选择性地改变花萼处的短期可塑性。用于实现这些目标的主要技术包括全细胞电生理学记录、脑切片中大量突触前 Ca2+ 负载以及 Ca2+ 瞬变的双光子成像。该提案的完成将提供对 PTP 在某个领域的功能作用的深入了解。 听觉脑干中的关键突触。 Wade Regehr 博士的专业知识和哈佛医学院的环境为我提供了完成我的目标所需的电生理学和成像技术方面的广泛培训。